Cancer appears in more than 100 different forms that affect nearly every part of the body. Throughout life, healthy cells in the body divide, grow, and replace themselves in a controlled fashion. Cancer results when the genes dictating this cellular division malfunction and cells begin to multiply and grow out of control. A mass or clump of these abnormal cells is called a tumor. Not all tumors are cancerous. Benign tumors, such as moles, stop growing and do not spread to other parts of the body. Cancerous or malignant tumors, however, continue to grow and smother healthy cells, interfere with body functions, and draw nutrients away from body tissues. Malignant tumors can spread to other parts of the body through a process called metastasis. Cells from the “mother tumor” detach, migrate via the blood or lymphatic vessels or within the chest, abdomen or pelvis, depending on the tumor, and they eventually form new tumors elsewhere in the body.
Cancer in the kidney constitutes about 3% of all solid tumors. About 85% of renal tumors are classified as renal cell carcinoma (RCC) Approximately 80% of diagnosed RCC originate from the epithelial cells lining the proximal parts of the kidneys' urine-forming ducts, the tubuli. Due to its appearance under the microscope, this cancer type is known as either renal clear cell carcinoma (RCCC, 65%) or renal papillary cell carcinoma (RPCC, 15%). While RCCC and RPCC constitute 80% of diagnosed RCC, they are responsible for closer to 100% of the deaths from renal cell carcinoma.
The most important factor in predicting prognosis is the stage. The stage describes the cancer's size and how deeply it has spread beyond the kidney. The Staging System of the American Joint Committee on Cancer (AJCC) is known as the TNM system. The letter T followed by a number from 1 to 3 describes the tumor's size and spread to nearby tissues. Higher T numbers indicate a larger tumor and/or more extensive spread to tissues near the kidney. The letter N followed by a number from 0 to 2 indicates whether the cancer has spread to lymph nodes near the kidney and, if so, how many are affected. The letter M followed by a 0 or 1 indicates whether or not the cancer has spread to distant organs.
Stage I: The tumor is 7 cm (about 2¾ inches) or smaller, and limited to the kidney. There is no spread to lymph nodes or distant organs.
Stage II: The tumor is larger than 7.0 cm but still limited to the kidney. There is no spread to lymph nodes or distant organs.
Stage III: Includes tumors of any size, with or without spread to fatty tissue around the kidney, with or without spread into the large veins leading from the kidney to the heart, with spread to one nearby lymph node, but without spread to distant lymph nodes or other organs. Stage III also includes tumors with spread to fatty tissue around the kidney and/or spread into the large veins leading from the kidney to the heart, that have not spread to any lymph nodes or other organs.
Stage IV: This stage includes any cancers that have spread directly through the fatty tissue and the fascia ligament-like tissue that surrounds the kidney. Stage IV also includes any cancer that has spread to more than one lymph node near the kidney, to any lymph node not near the kidney, or to any other organs such as the lungs, bone, or brain.
Detailed definitions of renal cell cancer, T, N, M categories, and stage groupings: Primary tumor (T):
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 7 cm or less, limited to kidney
T2: Tumor greater than 7 cm, limited to kidney
T3: Tumor extends into major veins/adrenal/perinephric tissue; not beyond Gerota's fascia
T3a: Tumor invades adrenal/perinephric fat
T3b: Tumor extends into renal vein(s) or vena cava below diaphragm
T3c: Tumor extends into vena cava above diaphragm
T4: Tumor invades beyond Gerota's fascia
N—Regional lymph nodes
NX: Regional nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in a single regional lymph node
N2: Metastasis in more than one regional lymph node
M—Distant metastasis
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
As a rule of thumb, cancer in stages I or II is treated by surgical removal of the afflicted kidney and the prognosis for recovery is good. Approximately 95% of all RCC are unilateral, meaning that the vast majority of all RCC patients are left with one remaining, healthy kidney after treatment. One functional kidney is generally considered more than enough for adequate glomerular filtration and general kidney function, meaning that patients with unilateral RCC in stages I or II are likely to live a perfectly normal life after treatment. For the remaining 5% of the patients, suffering from bilateral RCC, treatment often involves removal of both kidneys. This leaves the patient dependent on renal dialysis (hemodialysis or peritoneal dialysis) for life or until a renal transplant can be scheduled. If the tumors are small and well defined, kidney-conserving surgical techniques, involving partial removal of one or both kidneys, may leave bilateral RCC patients with sufficient remaining tissue to uphold normal or partial renal function. The benefits of these techniques (i.e. remaining renal function) must be weighed against the potential reoccurrence of RCC if even a microscopic part of the tumor escapes excision.
In contrast to the above, renal cancers of stage III or IV are associated with very low survival rates, and the National Cancer Institute states on its website that “Virtually no patients with renal cell cancer in stage IV can be cured.”
The National Cancer Institute estimates 49,096 new cases of renal cancer to have been diagnosed in the U.S. in 2009 (16/105 citizens) with 11,033 ensuing deaths (3.6/105 citizens). The corresponding numbers for the European Union (2006) are 65,051 diagnoses (7.8/105 citizens) and 27,326 deaths (3.3/105 citizens) (European Cancer Observatory: Estimated incidence and mortality 2006). Worldwide estimates (2006) are 209,000 diagnosed cases (3.2/105 citizens) and 102,000 deaths (1.6/105 citizens) (Gupta et al. Cancer Treat. Rev. 34, 193-205; 2008). The seemingly higher incidence in the U.S. is due to the fact that the NCI co-reports cancer of the renal pelvis (which is relatively easy to treat) with renal cell carcinomas. The lower global incidence and death rates are likely due, at least in part, to under diagnosis in large areas of the Third World.
The main problem with conventional art is that, as mentioned above, the outcome for any one patient diagnosed with renal cancer is dictated largely by the timing of the diagnosis. If the disease is diagnosed before the tumor has spread outside the kidney the chance for survival is good, otherwise most patients die from the disease. The main reason for this is that renal cell carcinoma is refractory to all conventional therapy with cytostatic and/or cytotoxic drugs, such as cisplatin, carboplatin, docetaxel, paclitaxel, flurouracil, capecitabine, gemcitabine, irinotecan, topotecan, etoposide, mitomycin, gefitinib, vincristine, vinblastine, doxorubicin, cyclophosphamide, celecoxib, rofecoxib, and/or valdecoxib.
Various solutions are described in the prior art. Conventional chemotherapy against renal cell carcinoma is generally contraindicated due to poor effectiveness and extensive side effects. Alternative treatment modalities have thus been sought, and they can be divided into several categories:
1) Antiangiogenesis. In this strategy the tumor is denied nutrients and oxygen through inhibition of formation of the blood vessels necessary for supplying the tumor tissue. This can be achieved in several ways: 1a) inhibition of circulating growth factors, such as VEGF, PDGF, and PIGF, by treatment with antibodies directed against these growth factors; 1b) blocking of receptors for vascular growth factors on target cells with antibodies directed against the receptors; and 1c) treatment with smaller molecules that interfere with receptor function in such a way that binding of a vascular growth factor to its receptor fails to elicit the physiological angiogenetic effect.2) Immunomodulatory treatment. This strategy attempts to stimulate the endogenous immune system to recognize the tumor cells as alien and start fighting them. Immune stimulation as treatment against renal cancer takes two main routes: 2a) treatment with interleukin 2 (IL-2); and 2b) interferon alpha (IFN-α) therapy.
All of the alternative treatment strategies mentioned above significantly improve the life span of some patients with renal cancer in an advanced stage. However, the effect is in the order of only a few months, and the treatment is associated with numerous serious side effects. Very often the tumor adapts to the treatment, which then has to be discontinued. This is followed by an accelerated rate of tumor growth.
Recent strategies for the treatment of renal cancer have been reviewed by Garcia et al., (“Recent progress in the management of advanced renal cell carcinoma.” CA Cancer. J. Clin. 57(2): 112-25 (2007)) and by Atkins et al. (“Innovations and challenges in renal cell carcinoma: summary statement from the Second Cambridge Conference.” Clin. Cancer. Res. 13(2 Pt 2): 667s-670s (2007)). A review of the literature indicated that many of the therapeutic approaches originate from the identification of more or less specific cancer markers and the use of these markers to elicit a host immune response directed against the invading tumor tissue. See for example, US2006134708 disclosing several molecular markers of kidney and urothelial cancer, namely IGFBP-3 (insulin-like growth factor-binding protein 3), ANGPTL4 (angiopoietin-like 4) and ceruloplasmin, as well as monoclonal antibodies directed against said markers, for diagnostic purposes.
U.S. Pat. No. 6,440,663 teaching different genes expressed by renal cancer cells and US 2005261178 teaching the co-administration of a monoclonal antibody (G250), directed against an antigen (carbonic anhydrase IX) expressed on the majority of renal cancers, and the cytokines Interleukin-2 or Interferon-α are other examples of such approaches.
Other strategies are based on the use of known therapeutic substances in new treatment regimes. For example, US20090131536 discloses the use of previously known dimethane sulfonate compounds, in particular NSC-281612, according to a new administration protocol in order to treat renal cancer. When tested on xenografts in nude mice, administration of NSC-281612 led, in some cases, to apparently complete eradication of the tumor mass.
Finally, in a few instances, suggested therapy is founded on new original substances. Thus, US20060025484 discloses the use of 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU) for the treatment of many cancer types, including renal cancer. The main feature of HECNU is an improved water solubility compared to the previously known corresponding compound, Bis-(2-chlorethyl)-1-nitroso-urea (BCNU).
EP1712234 discloses the use of 4-pyridylmethyl-phthalazine derivatives as VEGF receptor inhibitors in the treatment of renal cancer, especially for the inhibition of metastatic growth. It was found that co-administration of the 4-pyridylmethyl-phthalazine derivatives with either of a plurality of conventional chemotherapeutic agents had a synergistic effect, even though the tumor cells are refractory to the chemotherapy alone. Further, combination therapy was associated with noticeably smaller side effects.
The invention herein is based on Orellanine (Formula I), which is a selective renal toxin occurring in relatively large amounts in several fungal species of the Cortinarius family. Intoxication with Orellanine after confusion of Cortinarius fungi with edible mushrooms occurs regularly throughout Europe, Russia and North America. After ingestion of Orellanine-containing fungi, there is a period of a few days up to 3 weeks with no symptoms or only mild, influenza-like symptoms. The next phase, when medical help is generally sought, is characterized by uremia due to acute renal failure. Despite many descriptions of Orellanine poisoning in the scientific literature, no other effects of Orellanine have been reported apart from the renal toxicity just mentioned (Danel V C, Saviuc P F, Garon D: Main features of Cortinarius spp. poisoning: a literature review. Toxicon 39, 1053-1060 (2001).). This selectivity most likely resides with the fact that Orellanine is taken up specifically by one cell type, i.e., the tubular epithelial cells, particularly the proximal tubular epithelial cells (Prast H, Pfaller W: Toxic properties of the mushroom Cortinarius orellanus (Fries) II. Impairment of renal function in rats. Arch Toxicol 62, 89-96 (1988)). The toxin mechanism of Orellanine has not been elucidated, and no treatment is available except maintenance dialysis while waiting to see whether the kidneys will recover or not. The final outcome is critically dependent on the amount of toxin ingested, and, as a rule of thumb, ingestion of one fungus gives temporary problems, two fungi leads to permanent loss of part of the renal function whereas three or more fungi results in total loss of renal function and lifelong need for renal replacement therapy in the form of dialysis or kidney transplantation.
The applicants have recently published a first study of the mode of action of Orellanine in healthy rats (Nilsson U A et al. The fungal nephrotoxin orellanine simultaneously increases oxidative stress and down-regulates cellular defenses. Free Rad. Biol. Med. 44:1562-9 (2008).). This study shows increased oxidative stress in cortical renal tissue along with dramatically decreased expression of several key antioxidant genes. During this work it was realized that the specificity of Orellanine for renal tubular epithelial cells, which is in prior art generally considered to be absolute, could theoretically be extended to encompass these cells also after their transformation into cancer cells. If proven true, such a hypothesis would mean that Orellanine is a powerful weapon against renal cancer of epithelial origin, with curative potential even in advanced stages and with metastases in other tissues.
Pursuing this hypothesis, it was surprisingly discovered that Orellanine is indeed taken up also in human renal cancer cells, and kills them with great efficiency whether they are derived from a primary tumor or from metastatic tumor tissue. The cell death progresses for many days after transient exposure to Orellanine, indicating that the toxin is actively taken up and retained by the cells (see co-pending application US2010-0152243).
Although the discovery that Orellanine can target and kill renal cancer cells tremendously improved our ability to cure RCC in advanced stages, two significant drawbacks of the treatment are obvious:
Due to the target profile of Orellanine, treatment will inevitably lead to destruction of healthy renal tissue along with eradication of the metastatic tumor(s). This results in total renal failure, creating a need for life-long hemodialysis/peritoneal dialysis or kidney replacement by transplantation.
The notion of the high degree of specificity for Orellanine for normal (and transformed) renal tubular epithelial cells stems largely from intoxication data. In these cases a single dose of toxin was ingested in the form of mushrooms, and the vast majority of Orellanine in the ingested material was shunted to the kidneys simply by virtue of the extreme perfusion of these organs, receiving 20% of cardiac output. This means that Orellanine was rapidly filtered through the kidneys, and what was not taken up and retained by the tubular cells was lost in the urine. Consequently, the rest of the body was not exposed to significant concentrations of Orellanine. At least some of the observed specificity of Orellanine likely stems from this fact. Actually, the very fact that the toxin was taken up in to the bodies of those intoxicated clearly demonstrates that the specificity is not absolute; Orellanine must have been taken up and excreted into the blood by the epithelial cells lining the intestine. The setting during treatment for RCC is quite different: The overwhelming majority of the initial dose is eliminated through the kidneys, leading to the destruction of tubular cells and shutdown of remaining renal function. Subsequent doses, however, result in dramatically higher plasma concentration of Orellanine. This allows active uptake into the tumor cells of tubular origin, and these cells act, to some extent, as a sink that prevents exposure of other tissues to Orellanine. Nevertheless, spillover into other cell types is likely if high enough doses are used (as may be necessary to achieve total eradication of the tumor(s)). Thus, in spite of the apparent specificity of Orellanine, there may be collateral damage to other tissues when using it for treatment of RCC. This requires careful titration of the dose and regimen to balance the desired and undesired effects.
Accordingly there is a need for products and methods aimed to reduce the unwanted toxic effects of Orellanine in order to spare healthy renal tubular epithelial cells (and consequently renal function) as well as other cells that can be damaged by unspecific Orellanine toxicity. The present invention satisfies this need and provides further advantages as well.